The overall aim of this project is to investigate the contribution of polymorphisms in genes involved in estrogen biosynthesis and estrogen receptor function to rate of cognitive decline and risk of Alzheimer's disease (AD) in women with Down syndrome (DS). Prior studies in the general population suggest that the dramatic declines in estrogen levels following menopause may play an important role in the etiology of AD. Among women with DS, the average age at onset menopause is 46 and the average age at onset of AD is 50-55. Thus, in women with DS, the short interval between menopause and AD provides a unique opportunity to examine the influence of endogenous estrogen activity on disease risk in a prospective study. We hypothesize that women with genotypes associated with reduced levels of bioavailable E2 will have earlier onset and increased risk of AD. During our current study of women with DS, we have made several key observations: (a) earlier age at menopause was associated with earlier onset of AD in women with DS; (b) high levels of sex-hormone binding globulin and low levels of bioavailable estradiol were associated with earlier onset and increased risk of dementia. We now propose to expand our investigation of endogenous estrogen activity with new laboratory studies to identify genetic factors that may modify estrogen levels or estrogen activity and influence risk for AD. We will conduct a 5-year longitudinal study of in 336 women with DS, 40-59 years of age at baseline, followed at 18-month intervals. We will examine 5 candidate genes: ERalpha, ERbeta, CYP17, CYP19, and HSD17B1. We will determine whether polymorphisms in the genes for ERalpha (P and X), ERbeta (G), Cyp17 (Allele A2), CYP19 (TTTA repeat length) and HSD17B1 (A Allele) are (1) associated with differences in baseline levels and rates of change over time in systemic gonadal and steroid hormones; (i.e. serum estradiol, bioavailable estradiol, estrone, sex-hormone binding globulin, dehydroepiandrostcrone, follicle stimulating hormone and progesterone); (2) are predictors of the rate of decline in memory and related cognitive functions; and (3) are associated with earlier onset or increased risk of AD. The proposed studies will clarify biological mechanisms relating variations in estrogen to the development of AD.